There are two main characters in The House of the Dead Overkill, Agent G and his partner, Isaac Washington. Agent G has appeared in multiple games in the House of the Dead series, and has a enigmatic and cynical personality. Isaac Washington is a new character, and is a foul-mouthed cop with a bad attitude. The interplay between these two characters has been described as one of the most entertaining and explicit-laden parts of Overkill."GameSpot: The House of the Dead: Overkill Updated Hands-On

The House of the Dead Overkill is a prequel to the other games in the series, telling the story of Agent G's first mission as a special operative. He's partnered with a local detective named Isaac Washington to investigate a series of mysterious disappearances in a fictional Louisiana town called Bayou City, where a criminal named Papa Caesar is rumored to be located.

On the trail of Papa Caesar, Washington and Agent G end up encountering a zombie breakout. The game's action takes place as they move from locale to locale attempting to capture Papa Caesar and fight off hordes of zombies. Gameplay involves you shooting at the TV screen to fire on zombies. Point the Wii Remote on screen and aim, and press the B trigger to shoot and the A trigger to reload. Occasionally you'll be prompted to use the Wii's motion controls to fight some zombies off, like when an enemy climbs on your character and he needs to shake them off. As you kill zombies and collect money, you can buy new weapons and upgrades and use points to resurrect yourself.